Novel analogues of the therapeutic complement inhibitor compstatin with significantly improved affinity and potency

Hongchang Qu, Paola Magotti, Daniel Ricklin, Emilia L Wu, Ioannis Kourtzelis, You-Qiang Wu, Yiannis N Kaznessis, John D Lambris

Research output: Contribution to journalArticlepeer-review

Abstract

Compstatin is a 13-residue disulfide-bridged peptide that inhibits a key step in the activation of the human complement system. Compstatin and its derivatives have shown great promise for the treatment of many clinical disorders associated with unbalanced complement activity. To obtain more potent compstatin analogues, we have now performed an N-methylation scan of the peptide backbone and amino acid substitutions at position 13. One analogue (Ac-I[CVW(Me)QDW-Sar-AHRC](NMe)I-NH(2)) displayed a 1000-fold increase in both potency (IC(50) = 62 nM) and binding affinity for C3b (K(D) = 2.3 nM) over that of the original compstatin. Biophysical analysis using surface plasmon resonance and isothermal titration calorimetry suggests that the improved binding originates from more favorable free conformation and stronger hydrophobic interactions. This study provides a series of significantly improved drug leads for therapeutic applications in complement-related diseases, and offers new insights into the structure-activity relationships of compstatin analogues.

Original languageEnglish
Pages (from-to)481-9
Number of pages9
JournalMolecular immunology
Volume48
Issue number4
DOIs
Publication statusPublished - Jan 2011

Bibliographical note

Copyright © 2010 Elsevier Ltd. All rights reserved.

Keywords

  • Amino Acid Sequence
  • Complement Activation/drug effects
  • Complement Inactivator Proteins/chemistry
  • Humans
  • Kinetics
  • Molecular Sequence Data
  • Peptides, Cyclic/chemistry
  • Protein Binding/drug effects
  • Thermodynamics

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